Cerebral amyloid angiopathy (CAA) is most commonly associated with vascular deposition of amyloid-beta peptide (Abeta), as well as the presence of advanced glycation endproducts (AGEs), the irreversible products of non-enzymatic glycoxidation. One of the principal means by which Abeta and AGEs impact on vascular function is by interacting with cellular elements, especially endothelial (EC) and smooth muscle (SMC) cells, resulting in changes in cellular properties, and, in certain instances, cell death. Whereas Abeta and AGEs are structurally distinct and derive from different biochemical pathways, they share in common accumulation in CAA and recognition by Receptor for Advanced Glycation Endproducts or RAGE. Engagement of RAGE perturbs cellular functions resulting in sustained oxidant stress, activation of the transport factor NF-kappaB, and, in certain instances, apoptosis. We hypothesize that CAA occurs, in part according to a "two-hit" model; the first hit is comprised of sustained Abeta/AGE binding to and activation of cellular RAGE; and the second hit includes superimposed environmental challenges such as intermittent ischemia, as in stroke. The focus of Project 3 is to dissect the contribution of RAGE in SMCs to vascular dysfunction in CAA since RAGE is expressed at highest levels in vascular SMC, which is in intimate contact with accumulated Abeta and AGE-modified matrix, and SMCs are known to undergo degeneration in cerebrovascular amyloidosis. The first aim of Project 3 is to determine if transgenic mice with targeted over expression of wild-type RAGE in SMCs display enhanced vascular perturbation, eventuation in disruption of the vessel wall in Abeta- and/or AGE-rich vascular micro environment. The second aim is to determine if transgenic mice with targeted over expression of wild-type RAGE in SMCs display enhanced vascular perturbation, eventuating in disruption of the vessel wall in Abeta-and/or AGE-rich vascular micro environment. The second aim is to determine if transgenic mice with targeted over-expression of dominant negative 9DN) RAGE are protected from vascular perturbation by Abeta and AGEs. The long-term goal of Project 3 is to determine the role of RAGE in CAA in order to evaluate whether antagonism of Abeta-AGE interaction with this receptor is a therapeutic target for patients with chronic cerebrovascular dysfunction.